The prognostic utility of prehospital qSOFA in addition to emergency department qSOFA for sepsis in patients with suspected infection: A retrospective cohort study

Background The quick sequential organ failure assessment (qSOFA) was widely used to estimate the risks of sepsis in patients with suspected infection in the prehospital and emergency department (ED) settings. Due to the insufficient sensitivity of qSOFA on arrival at the ED (ED qSOFA), the Surviving Sepsis Campaign 2021 recommended against using qSOFA as a single screening tool for sepsis. However, it remains unclear whether the combined use of prehospital and ED qSOFA improves its sensitivity for identifying patients at a higher risk of sepsis at the ED. Methods We retrospectively analyzed the data from the ED of a tertiary medical center in Japan from April 2018 through March 2021. Among all adult patients (aged ≥18 years) transported by ambulance to the ED with suspected infection, we identified patients who were subsequently diagnosed with sepsis based on the Sepsis-3 criteria. We compared the predictive abilities of prehospital qSOFA, ED qSOFA, and the sum of prehospital and ED qSOFA (combined qSOFA) for sepsis in patients with suspected infection at the ED. Results Among 2,407 patients with suspected infection transported to the ED by ambulance, 369 (15%) patients were subsequently diagnosed with sepsis, and 217 (9%) died during hospitalization. The sensitivity of prehospital qSOFA ≥2 and ED qSOFA ≥2 were comparable (c-statistics for sepsis [95%CI], 0.57 [0.52–0.62] vs. 0.55 [0.50–0.60]). However, combined qSOFA (cutoff, ≥3 [max 6]) was more sensitive than ED qSOFA (cutoff, ≥2) for identifying sepsis (0.67 [95%CI, 0.62–0.72] vs. 0.55 [95%CI, 0.50–0.60]). Using combined qSOFA, we identified 44 (12%) out of 369 patients who were subsequently diagnosed with sepsis, which would have been missed using ED qSOFA alone. Conclusions Using both prehospital and ED qSOFA could improve the screening ability of sepsis among patients with suspected infection at the ED.


Introduction
Early identification of suspected sepsis and initiation of appropriate management play a crucial role in reducing the mortality of sepsis [1,2]. To screen patients at high risk of sepsis among patients with suspected infection at the emergency department (ED), the Sepsis-3 Task Force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score (i.e., qSOFA �2 should be considered as suspected sepsis) [3], a simple algorithm that has been widely used in the ED setting. Moreover, as qSOFA was originally developed for use outside the intensive care unit (ICU), discussions have been made to improve the quality of triage by using qSOFA in the prehospital setting [4][5][6][7].
Despite the initial recommendation to use qSOFA by the Sepsis-3 Task Force, several studies have shown that qSOFA is more specific but less sensitive compared with other screening tools (e.g., the systemic inflammatory response syndrome [SIRS] criteria) in predicting prognostic outcomes related to sepsis [8][9][10][11][12]. Thus, the Surviving Sepsis Campaign 2021 recommended against using qSOFA as a single screening tool for sepsis or septic shock [13].
The advantage of qSOFA is its simplicity compared to other scoring systems for estimating the risk of sepsis (e.g., SIRS criteria, National Early Warning Score [NEWS]). Thus, it would be valuable to devise a new scoring system that improves on qSOFA with its simplicity preserved. As Keivlan et al. reported that repeated measurements of qSOFA improved its predictive validity for sepsis compared to a single measurement of qSOFA [14], it may be beneficial to consider the combined use of prehospital and ED qSOFA for accurately screening patients at a higher risk of sepsis on arrival at the ED. Nonetheless, it remains unclear whether the combined use of prehospital and ED qSOFA improves its sensitivity for identifying patients at a higher risk of sepsis at the ED.
To address this knowledge gap in the literature, we aimed to clarify whether the addition of prehospital qSOFA to ED qSOFA improves the predictive ability for sepsis in patients with suspected infection at the ED compared with the use of prehospital qSOFA or ED qSOFA alone.

Study design and setting
This is a retrospective cohort study using data from the ED of Hitachi General Hospital from April 1, 2018, to March 31, 2021. Hitachi General Hospital is a tertiary medical center in Japan that covers a population of approximately 3 million people and has approximately 20,000 ED visits annually. The medical records are structured through an electronic medical information system (the NEXT Stage ER system, TXP Medical Co. Ltd., Tokyo, Japan), which supports healthcare professionals including ambulance officers entering clinical information as structured data [15]. The study protocol was approved by the ethics committee of Hitachi General Hospital, which waived the requirement for informed consent due to the retrospective nature of the study.

Study participants
We identified adult patients (aged �18 years) with suspected infection transported to the ED by ambulance and initially treated by emergency medicine physicians. We defined suspected infection based on the chief complaint of fever, high body temperature (�37.5˚C), or ED diagnosis of infection (e.g., pneumonia, urinary tract infection, cellulitis, pharyngitis, and meningitis). The diagnosis of infection was inferred from each patient's clinical context on arrival at the ED, which was routinely recorded by emergency physicians at Hitachi General Hospital and automatically converted to the International Classification of Diseases (ICD) -10 codes by the algorithm of the NEXT Stage ER system [15]. We excluded the following patients from the analysis: patients who had trauma or cardiac arrest [16], died immediately upon arrival at the ED, were transported to other hospitals after the ED arrival, and had six or more missing parameters out of seven vital sign parameters (systolic blood pressure [ (Fig 1).

Measurements
For each enrolled patient, we collected patient age, sex, vital signs both in the prehospital and ED settings (sBP, dBP, HR, RR, BT, altered mental status [GCS �14], and SpO 2 ), receipt of oxygen therapy upon arrival at the ED, and disposition (discharge from the ED, ICU admission, and in-hospital mortality). For patients admitted to the ICU, all data on laboratory tests (e.g., serum creatinine, total bilirubin, platelet count, and serum lactate level), microbiological blood culture tests, and the use of medications (e.g., antibiotics and vasopressors), and mechanical ventilators were also collected to determine the presence of sepsis based on the sepsis clinical surveillance definition (S1 Appendix) [17].

Outcome measures
The primary outcome was the diagnosis of sepsis based on the Sepsis-3 criteria [3]. We identified patients with sepsis using the modified sepsis clinical surveillance definition (shown in S1 Appendix) instead of using the original Sepsis-3 criteria, since we had difficulty accurately identifying patients with sepsis based on the Sepsis-3 criteria (i.e., �2-point increase in SOFA score) in the current study due to its retrospective nature. We utilized the definition of sepsis based on the criteria initially proposed by Rhee et al. [17], which was to define sepsis based on the Sepsis-3 criteria in retrospective studies [18,19]. At Hitachi General Hospital, as a general practice, patients who visit the ED that need to be hospitalized are first treated by intensivists in the ICU, and then stepped down depending on their medical condition. In other words, all patients with suspected infection at the ED are always admitted to the ICU (i.e., not initially admitted to the general wards) for treatment in our hospital system. Therefore, in this study, we identified patients subsequently diagnosed with sepsis admitted to the ICU, which means all patients with sepsis hospitalized via the ED [19,20].

Statistical analyses
We computed summary statistics to delineate the characteristics of all patients with suspected infection. All the data we used for the calculation of qSOFA, including the number of missing data, are shown in Table 1. In order to minimize the selection bias induced by the missing data, the random forest method was applied to impute all the missing vital signs data using the following variables: age, sex, vital signs both at prehospital and ED arrival (sBP, dBP, HR, RR, BT, GCS, and SpO 2 ), receipt of oxygen therapy upon arrival at the ED, and outcomes (i.e., sepsis, septic shock, and in-hospital mortality) [21][22][23]. After the imputation of all the missing vital signs data, we calculated both the prehospital and ED qSOFA.
To verify our findings, we performed a sensitivity analysis using septic shock and in-hospital mortality as prognostic outcomes related to sepsis. We calculated c-statistics and prospective prediction results and compared the predictive abilities of prehospital qSOFA, ED qSOFA, and combined qSOFA for septic shock and in-hospital mortality, all in the same manner as the primary outcome.
All analyses were conducted using R version 4.1.0 (R Foundation, Vienna, Austria) [25]. A P-value less than 0.05 was considered statistically significant.

Patient characteristics
Among 10,773 patients who were transported by ambulance to the ED of Hitachi General Hospital from April 2018 to March 2021, we identified 2,407 patients with suspected infection whose prehospital and ED vital signs data were available. The flow chart of the study participants' selection process is shown in Fig 1. The median age (IQR) was 78 (67-85) years, and 1,393 (58%) were male. Of these, we identified 369 (15%) patients who developed sepsis, 133 (6%) patients who developed septic shock, and 217 (9%) patients who died during hospitalization. ( Table 2).

Main results
The predictive ability of prehospital qSOFA for sepsis was almost equivalent to that of ED qSOFA (c-statistics of prehospital qSOFA versus ED qSOFA for sepsis [

Prehospital vital signs
Systolic blood pressure 186 (8) Diastolic blood pressure 224 (9) Heart rate 47 (2) Respiratory rate 262 (11) Body temperature 181 (8) Altered mental status [GCS �14] 56 (2) Abbreviations: ED, emergency department; GCS, Glasgow Coma Scale; qSOFA, The quick Sequential Organ Failure Assessment � All missing data were imputed with the random forest method. In our analyses, we imputed all qSOFA using all vital signs data with multiple imputation estimations by the random forest method. Altered mental status was defined as the GCS �14. https://doi.org/10.1371/journal.pone.0282148.t001 using combined qSOFA, we were able to identify 44 (12%) out of 369 patients who were subsequently diagnosed with sepsis who would otherwise have been missed using ED qSOFA alone.

Sensitivity analysis
Similar results were obtained for the predictive performance of septic shock and in-hospital mortality as that of sepsis (Tables 4 and 5). For instance, the predictive performances for septic shock and in-hospital mortality of prehospital and ED qSOFA were also comparable (e.g., cstatistics of prehospital qSOFA versus ED qSOFA for in-hospital mortality  shock and in-hospital mortality of prehospital qSOFA, ED qSOFA, and combined qSOFA are shown in Fig 2. Overall, a cutoff value of 3 for combined qSOFA is appropriate for predicting septic shock and in-hospital mortality as well as sepsis in our primary analysis.

Discussion
In this retrospective study of 2,407 adult patients with suspected infection transported by ambulance to the ED of a tertiary medical center, we found that the sum of prehospital and ED qSOFA �3 achieved a higher sensitivity of predicting sepsis based on the Sepsis-3 criteria at the ED compared with prehospital qSOFA �2 and ED qSOFA �2 alone. By using prehospital qSOFA in combination with ED qSOFA, we were able to identify 44 (12%) out of 369 patients  with sepsis who would have been missed by ED qSOFA alone. Additionally, this is the first study to investigate the predictive ability of qSOFA in the prehospital and ED setting for the diagnosis of sepsis based on the Sepsis-3 criteria without using any surrogates (e.g., ICD-9 codes and ICD-10 codes) [26][27][28].
To enhance the quality of prehospital triage, the use of prehospital qSOFA has been discussed. Previous studies showed that prehospital qSOFA was significantly associated with poor prognosis (e.g., in-hospital mortality, ICU admission, and length of ICU stay) in patients with sepsis [4,5,26,29]. Indeed, the predictive abilities for sepsis of prehospital qSOFA and ED qSOFA were comparable in our study, suggesting the potential utility of prehospital vital signs on triage. On the other hand, the usefulness of qSOFA as a screening tool for patients likely to have sepsis has been controversial, as several studies pointed to the insufficient sensitivity of using ED qSOFA alone (16 to 54%) [7,12,30], which is also consistent with our results. Hence, the Surviving Sepsis Campaign 2021 has recommended against using qSOFA as a single screening tool for sepsis [13]. However, given the simplicity of qSOFA and sufficient sensitivity of combined qSOFA, the additional use of prehospital qSOFA to ED qSOFA may be a practical way of screening patients for sepsis on arrival at the ED. Considering that repeated measurements of qSOFA were found to improve predictive validity for sepsis in a previous study [14], our results suggest that prehospital and ED vital signs are particularly suitable for two-point measurements to screen the risk of sepsis, which physicians can easily access at the time of ED triage. Our findings extend prior studies by devising a simple and sensitive screening method-the simultaneous use of prehospital qSOFA and ED qSOFA-for sepsis based on the Sepsis-3 criteria in patients with clinically suspected infection at the ED.
The higher sensitivity of the addition of prehospital qSOFA to ED qSOFA to screen for sepsis compared to ED qSOFA alone could be because the combined qSOFA was able to pick up more patients subsequently diagnosed with sepsis among those with qSOFA <2 on arrival at the ED (e.g., patients with prehospital qSOFA of 2 and ED qSOFA of 1). Given the high morbidity and mortality of sepsis [31], the additional use of prehospital qSOFA, which could easily screen as many as an additional 12% of patients at a higher risk of sepsis, is of great significance. Although ED qSOFA �1 was more sensitive for the diagnosis of sepsis than ED qSOFA �2 or combined qSOFA �3, the ED qSOFA cutoff of 1 is not suitable for clinical use due to its high false positive rate. Therefore, combining prehospital and ED qSOFA may be clinically more beneficial than using ED qSOFA alone.

Limitations
Our study has several limitations. First, as the relationship between vital signs in the prehospital and ED settings may depend on ambulance transport time, further studies are required to investigate whether our findings could be affected by this. Second, our vital signs data contained missing data (2%-33% of the data depending on the variable), which could be a potential source of bias. However, we believe this problem was minimized by using random forest imputation after the exclusion of patients with mostly missing vital signs [21][22][23]. Third, because all the data on the ED visits were retrospectively collected, there could have been misclassification. However, all the data used in this study were structured by the NEXT Stage ER system, and most of the data were coded with sensitivity and specificity greater than 90% (e.g., chief complaints, comorbidities, medications, and physician diagnoses) [15]. Lastly, since this study was retrospectively conducted in a single center, our findings may have limited transportability. Larger studies involving multiple facilities with different emergency medical systems (e.g., a hospital located in an urban area surrounded by several hospitals) are warranted to validate our findings.

Conclusions
We found that using prehospital qSOFA in addition to ED qSOFA could efficiently screen patients with suspected infection at the ED for sepsis. Given the limited patient information available on arrival at the ED, prehospital vital signs may be useful in estimating the risk of sepsis in patients with suspected infection.
Supporting information S1 Appendix. The modified sepsis clinical surveillance definition. According to the Sepsis-3 criteria, sepsis is defined as life-threatening organ dysfunction due to infection, and can be defined as an increase in the Sequential Organ Failure Assessment (SOFA) score of �2-point.